Prostate cancer (PCa) is the most common male cancer in many industrialized countries1,2. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen ablation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castration resistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens3. Mechanisms of CRPC progression include AR amplification and overexpression4,5, AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (AR-Vs)6, and induction of intracrine androgen metabolic enzymes3, 7.
The canonical human AR has 919 amino acids with a mass of 110 kDa, composed of four structurally and functionally distinct domains including the N-terminal domain (NTD, amino acids 1-537), DNA-binding domain (DBD, amino acids 537-625), hinge region (amino acids 625-669) and ligand binding domain (LBD, amino acids 669-919)8. When activated by endogenous androgens, AR translocates into the nucleus, associates with co-regulatory factors, and binds to specific genomic DNA sequences in the regulatory regions of AR target genes9. Previous clinical research showed that targeting AR was a valid therapeutic strategy for CRPC10. Indeed, recent clinical trials have shown that the AR antagonist MDV3100 (MDV)11 and abiraterone, an inhibitor targeting androgen synthesis12, are effective against CRPC. However, recent studies have reported that AR-Vs which lack the ligand binding domain (LBD) are resistant to anti-androgen therapy including MDV and abiraterone13, 14, 15, 16, 17. Since the major AR-Vs identified to date have an intact NTD and DBD, they display constitutive activity, which underlies the persistent AR signaling in CRPC expressing these variants6, 18, 19, 20. Collectively, both ligand-dependent full-length AR (AR-FL) and AR-Vs mediate distinct transcriptional programs in CRPC21, 22, 23, but AR inhibitors currently in clinical use all target the LBD, and thus would not overcome cancer cell resistance driven by constitutively active AR-Vs.
AR is maintained in a ligand binding-competent state through its interaction with the foldosome, a protein complex consisting of the chaperones HSP40, HSP70 and HSP90 together with the co-chaperones HOP, p23 and the immunophilins FKBP51/52 and BAG-124. Intriguingly, some inhibitors of HSP90 such as AT13387 decrease the expression of several HSP90 client proteins including wild-type AR and AR-V7 (an AR splice variant), and also disrupt nuclear localization of the AR. A phase I/II clinical trial of AT13387 alone or in combination with abiraterone acetate in patients with mCRPC is in progress25. Other HSP90 inhibitors that target the AR N-terminus including NVP-HSP990 and PF-04929113 have activity in preclinical studies26, 27. The co-chaperone p23 is over-expressed in multiple types of cancer, and protects cancer cells from HSP90 inhibitors28. p23 over-expression is induced upon treatment with either androgens or anti-androgens and facilitates PCa cell motility; p23 knockdown inhibits the invasiveness of the PCa cell line LNCaP, suggesting an important role of p23 in PCa. metastasis independent of its role as an HSP90 co-chaperon29. The expression of p23 increases AR protein level, AR ligand binding activity, and AR's target promoter-binding activity; most importantly, p23 functions to promote AR activity in an HSP90-independent mechanism involving the direct binding to AR30. p23 is also associated with an increased resistance to etoposide and doxorubicin in breast cancer cells31 along with elevated expression of a subset of estrogen-responsive genes32. p23 over-expression correlates with poor prognosis for breast cancer patients, implicating p23's role in breast cancer progression in addition to PCa, supporting the utility of p23 as a potential therapeutic target for cancer therapy.
Therefore there is a need for compounds that block the transcriptional activities of both ligand-dependent AR-FL and constitutively active AR-Vs.